STEVE
USDIN: This week, R&D leaders from three companies discuss the search for
medical breakthroughs and what a government initiative could mean for children
with a crippling bone disorder and patients with cancer. I'm Steve Usdin.
Welcome to BioCentury This Week.

STEVE
USDIN: It's been a long-sought goal of medical science, treatments that
precisely address the root causes of disease. They're called targeted
therapies. And now, the FDA is seeing a flood of them on the horizon. Last
week, we heard FDA's top drug regulator, Dr. Janet Woodcock, describe how the
agency's new Breakthrough Therapies program aims to get these treatments into
the hands of physicians as quickly as possible.

This
week, we'll see how several drugs in the FDA's program actually could be
breakthroughs. We'll see how inventions from a Biotech company, Alexion
Pharmaceuticals, and two pharma giants, Novartis and Johnson & Johnson
promise to change cancer and a rare disease that prevents bones from forming
properly.

We
start with Asfotase Alfa, a drug the FDA has designated as a breakthrough for
hypophosphatasia, or HPP, an ultra-rare genetic disorder. Infants with HPP have
soft, demineralized bones that lead to disfigurement, organ problems, and often
death. X-ray images of a baby's hand before and 24 weeks after receiving Asfotase
Alfa provide a stunning glimpse of how this breakthrough candidate could
transform the lives of these children.

We're
joined by Dr. Martin Mackay Executive Vice President and Global Head of R&D
at Alexion, the biotech company that's developing Asfotase Alfa. Dr. Mackay so
we've got these X-ray images can you describe just what we're seeing there?

DR.
MARTIN MACKAY: Yes, indeed. This was actually part of our Phase II study that
was conducted by Dr. Michael White in patients with hypophosphatasia. The two
panels here show perinatal patient. And on the left hand panel, you see the
bone malformation. So basically, the baby doesn't have proper bones -- and in
this case, his fingers. And then, on the right hand panel, after 24 weeks of Asfotase
treatment, you see this remarkable improvement.

STEVE
USDIN: So taking a step back, what is HPP? What causes it? And how common is
it?

DR.
MARTIN MACKAY: Well, it's a devastating disease, no question. It is ultra- rare,
as you mentioned. It's an inherited disease with quite profound effects on
patients. It's shown that it can happen in the perinatal stage, in infants, and
juveniles, and even adults.

With
the earliest stages, with the perinatal and infants, it has quite a profound
effect on the patient. The radiographs show that on the fingers. But can you
imagine the same for ribs? Where you see radiographs and the baby doesn't have
ribs? And what that leads to in terms of bone malformation and respiratory
problems? So this is why we are working on a treatment for it.

STEVE
USDIN: In some of your early studies, also, you've seen babies, even, and
toddlers, who couldn't walk, and who were able to walk and function as a result
of receiving this therapy. It's really amazing. How was Asfotase Alfa
discovered, and what's your development path going forward?

DR.
MARTIN MACKAY: Yes. So we know what causes HPP. That's good news. And it's
actually an enzyme that's missing from the patient. And the enzyme's called
Tissue Nonspecific Alkaline Phosphotase. And what happens, because that is
deficient, it causes the buildup of other chemicals in the body. And it's those
other chemicals that cause the damage to bones and respiratory failure.

So
there were some early studies done with a notion of replacement -- just give
the patient Alkaline Phosphotase. But unfortunately, that didn't work very
well. Our scientists, on the other hand, engineered Alkaline Phosphotase. And
what they added to the enzyme was another part of the molecule, which allowed
the molecule to get to the place where it needs to be and to deliver it to the
bones. And it was that time, as shown in those radiographs, where we saw the
remarkable benefits.

STEVE
USDIN: So this is an ultra-rare disease. There's probably 2,000 or 3,000
children a year born in the United States with this condition. How many
patients have you studied now, and how many more do you think that you'll have
to study before you can get approval for it?

DR.
MARTIN MACKAY: Yep, so a couple of points. We don't actually know the total
number of patients. We know it's ultrarare. But one of the things that you
notice is, when you come along with a treatment, and an effective treatment, a
treatment that really transforms the lives of patients, you understand the
disease better.

But
there's no question it's small numbers of patients. That's the area that we
work in. We have treated over 50 patients with Asfotase Alfa. And we do see
profound effects in those patients. The response rates have been terrific, to
date.

In
terms of what the development path is, we continue with our studies. And one of
the things I'm sure we'll discuss is this breakthrough designation and what
that means?

STEVE
USDIN: Yeah, so what does it mean?

DR.
MARTIN MACKAY: You know it's relatively early to say. We were given this
designation just a couple of weeks ago. A, we're absolutely thrilled by it
because it plays into the area that we work in Alexion -- you know, ultra rare
devastating disease.

What
we expect it will mean is a very good discussion with the FDA, and a continual
discussion as we go through the development path. That's going to be very
important to us in terms of the development pathway for Asfotase Alfa. So we
really welcome this.

STEVE
USDIN: So very quickly, also, this is another issue, which is a kind of
controversy about some of these drugs for ultra-rare conditions, which is the
pricing and access. Your other drug that you've already got approved, Soliris,
costs more than $400,000 a year. Do you expect that Asfotase Alfa will have
similar pricing? And how do you ensure that people who don't have insurance, or
can't afford it, can access them?

DR.
MARTIN MACKAY: So in terms of Asfotase Alfa, it's really too early to think
about pricing. I mean, we are just absolutely devoted to developing this
medicine and getting it to the patients that it needs. But you raise an
interesting point about Soliris, or eculizumab. We've been successful now
talking to over 50 countries, both public and nonpublic payers, to make sure
that eculizumab -- Soliris -- gets to the patients that need it.

STEVE
USDIN: So Dr. Mackay, Soliris is expected to generate about $1.5 billion in
revenues for Alexion this year. The pricing is north of $400,000 per patient.
You're working on four or five other ultra-rare diseases, and there are
hundreds, maybe, thousands of them. Is it going to be sustainable, do you
think, for the healthcare system to have those kinds of pricing for all of
these, if we're lucky enough to find therapies for them?

DR.
MARTIN MACKAY: Yeah, the way I look at this is, the diseases that we work in
are devastating. If you think about patient where the prognosis is so poor in
so many cases, that whole aspect of access is very important to us. What's
equally important to us, though, is how good our medicine is.

And
I like to look at it this way as, how bad and how good? How bad is a disease?
And for us to work in it, it has to be devastating. And how good is our
medicine? We're not looking for incremental benefits here. We're looking for a
profound difference in the patient's lives. You caught a glimpse of that with
the radiographs. So you put that together, it's really important, as companies,
that we work in this space and get those medicines to the patients that need them.

STEVE
USDIN: Another thing I'm wondering about -- for Soliris, for example, one of
the things that's interesting, when it's for an ultra-rare condition, but,
actually, it's for now, what? Two ultra-rare conditions. And you're looking at
other ones. It's a drug that affects the complement system, sort of the flip
side of the inflammatory system. Couldn't a drug like that, either that drug,
or one that would be similar to that, have much broader applications? Can you
learn things from these ultra-rare conditions that could be applied to more
broad conditions?

DR.
MARTIN MACKAY: That's certainly possible. That's not what we do. We are very
much focused on the ultra-rare diseases and the two that you mentioned, for
eculizumab -- Soliris -- PNH, and Atypical HUS. And they fit into this very
well. They are ultra-orphan. They're devastating for patients.

The
really good news is eculizumab makes a profound difference to those patients.
We have real expertise. Our scientists at Alexion know complement very well.
And that's why we look for other ultra-orphan diseases where complement plays a
role. And as you mentioned, we've got a number of programs earlier in
development.

STEVE
USDIN: What's it what's the difference in developing a drug for an ultra-orphan
disease compared to developing one for a more common disease?

DR.
MARTIN MACKAY: Well, I think this goes right across whether it's a small, it's
ultra-orphan, that we work in, or larger, it's really understanding the path of
physiology of disease.

STEVE
USDIN: Thanks. In a moment, we'll hear about a potential breakthrough treatment
for lung cancer. First, here's a snapshot of the growing cohort of therapies in
the FDA's breakthrough drug program.

NARRATOR:
You're watching BioCentury This Week.

SEGMENT 2

STEVE
USDIN: Most of FDA's breakthrough candidates are very precisely targeted.
Novartis' LDK 378 is a good example. And early studies have produced dramatic
results for patients with lung cancer tumors that are driven by a specific gene
mutation. To discuss LDK 378 and the development of breakthrough targeted
cancer drugs, we're joined by Hervé Hoppenot, President of Novartis Oncology.
Mr. Hoppenot, maybe the best way to start is by talking about this gene
mutation. What is it, and how does it allow you to segment out certain lung-cancer
patients for this kind of treatment?

HERVÉ
HOPPENOT: The history of the LDK development is very symbolic of what we have
been trying to do at Novartis. In fact, since the Gleevec story, 15 years ago
at most. And the LDK story started 10 years ago, when ALK was identified.

And
a little bit later, in a group of patients with lymphoma. And a little bit
later, it was also found in patients with non-small cell lung cancer. And 10
years ago, on 2003, 2004, a program was started to target that new oncogenic
target that was just identified.

And
through these six or seven years of finding, identifying, standardizing, the
best drug, LDK came out at the end of the process as the best potential
candidate. And we started clinical studies in 2011. So there's a group of
patients with non-small cell lung cancer, between 3% and 8%, who have this
abnormal gene, and where we know this drug could be of great benefit.

STEVE
USDIN: So what were the kind of results you've got that led you to apply and
led FDA to grant breakthrough designation with LDK 378?

HERVÉ
HOPPENOT: Yeah, what makes it really symbolic of modern oncology development is
that we are able to start the first studies, the first in man in patients who
have the abnormality that we are targeting.

STEVE
USDIN: So you knew that it was likely to work in them?

HERVÉ
HOPPENOT: We hoped it is working. But what's more interesting is that we are
able, first, to do the study in patients who could benefit from the treatment,
which is obviously one of the big advantages. And from the development
standpoint, we do the dose escalation, and we have, in fact, a proof of concept
all in the same study.

And
that's what happened with LDK. It's not always the case. In that case, it was
successful. We were able to expand the study. Now we have around 114 patients
that have been included. And we were able to see around 400 milligram dose so
somewhere halfway in the dose escalation, that we had very dramatic responses
already.

So
then we continued to adjust the dose and to find what's best dose that we can
use for this product. And now we are around 750 milligram. And we know it's a
dose that will be very effective for this patient with that very specific
translocation that we discussed.

STEVE
USDIN: So you've gotten this breakthrough designation. What does that mean?
What is going to change as a result of that? What's going to happen that
wouldn't have happened without breakthrough designation?

HERVÉ
HOPPENOT: It's difficult to know because we are in the middle of learning how
this process is working. The accelerated review process did exist already for a
number of years. We had a number of our own products that went through it and
could lead to, relatively, a very rapid approval in the US. What we hope will
come out of the breakthrough designation is the ability to have a dialogue with
the FDA, to be able to align with them prior to the filing on what they really
need to be able to review the file and give us approval.

You
know, the old process, even through the accelerated review process, is a
process where we accumulate all the data, we go to the FDA, they review it, and
they tell us good or bad. In that case, we have a period of time between now
and filing where we can meet with them, we can align on what they need, and I
think it can be been very beneficial, specifically for products that go very
quickly through the development process, because a number of questions are not
really clinical questions. A number of questions are about chemistry,
stability, industrialization that needs to be done very quickly and where I
think it's very beneficial to have a dialogue with FDA and to be able to
calibrate with them what would be required so that they can give us a good
outcome to the finding.

STEVE
USDIN: And so, very briefly, also about the results that you've gotten from it --
this is the second, actually, ALK inhibitor for non-small cell lung cancer. The
other one is Xalkori from Pfizer. What's the difference between LDK 378, based
on your early results, and the first one that was approved for this same
subpopulation?

HERVÉ
HOPPENOT: So we know the targeting is different. So that sort of the
pre-clinical profile of the two drugs is very different. We don't know the
clinical difference head-to-head. But what we know is that the first activity
that was seen was in patients who were previously exposed to Crizotinib and
we're progressing, and then were responding, again, to LDK. So it was effective
in patients --

STEVE
USDIN: Who failed the other ALK inhibitor. Well, thank you. The roster of
breakthrough drugs is dominated by cancer therapies. Johnson & Johnson's
received four breakthrough designations for cancer drugs. We'll talk about them
in a moment.

SEGMENT 3

NARRATOR:
Now, back to BioCentury This Week.

STEVE
USDIN: Johnson & Johnson's been awarded four breakthrough designations for
cancer drugs. Three are for a single molecule, which Johnson & Johnson's
developing for B-cell cancers in partnership with a biotech company,
Pharmacyclics. J&J also received breakthrough designation on the basis of
dramatic data in treating multiple myeloma.

I'm
pleased to be joined today by Dr. Jay Siegel head of global regulatory affairs
for Janssen R&D, part of J&J. Dr. Siegel worked for 20 years at the FDA
center for biologics, including seven years as head of its Office of
therapeutics research and review. Dr. Siegel, let's start with the first
breakthrough designation for Ibrutinib Can you tell me, what was the basis for
the FDA giving you that designation? What could it mean for patients if it gets
approved?

DR.
JAY SIEGEL: Right, so the first the designation for Ibrutinib it was in mantle
cell lymphoma, which is a particularly difficult to treat type of non-Hodgkin's
lymphoma -- as you said, a cancer of a type of lymphocyte, the B lymphocytes
that circulate in the bloodstream.

This
particular disease is problematic because it is both relatively aggressive
among lymphomas, and, unlike some other aggressive lymphomas, it's particularly
resistant to therapy. So once the disease relapses, or fails to respond to the
first treatment, there are not many options available. One approved drug,
bortezomib, or Velcade, that we're involved in developing, other drugs that are
experimental.

But
pretty much, they cause responses that are rather short lived and occur in a
minority of patients. In the earliest studies in this population with Ibrutinib,
we saw remarkable, unparalleled types of results, with approximately 70%,
almost 70%, of patients responding -- with over 20% having complete response,
having evidence of their disease disappear compared to say single digit type
responses with other drugs.

STEVE
USDIN: And you've got some other indications but they're also similarly, for Ibrutinib,
they're in B-cell cancers. There's another drug that you've received breakthrough
designation for that's for multiple myeloma. Can you tell us about that one?

DR.
JAY SIEGEL: Yes that's Daratumumab. It's a monoclonal antibody. It's also a
partnership with Genmab, although it's a licensing arrangement. And we're
responsible for the development.

And
it's earlier in development. But even in its first clinical trials, in patients
in multiple myeloma, we treated highly refractory patients. These are people
who have failed three lines of therapy, or have failed to respond to the two
most critically invaluably important types of drugs for this disease. And in
those patients, their typical life expectancy is significantly under a year.

And
we found, even in the first -- just treated about 30 patients -- and only 12 at
doses high enough where we would expect to see any sort of activity of the drug
and are extremely pleased with the types of responses we saw. Of those 12,
about five or so having very good responses, in terms of the abnormal proteins
in their serum, even larger numbers having very good responses in terms of the
growth of the tumor cells in their bone marrow.

STEVE
USDIN: So can you talk a little bit about what breakthrough status,
breakthrough designation, might mean for either one of these drugs. What might
happen that wouldn't have happened without breakthrough status?

DR.
JAY SIEGEL: Sure. Well, breakthrough is, of course, an early program. So the
answers to that remain not yet fully defined. But Ibrutinib, especially in its
first indication, a mantle-cell lymphoma, was one of the first breakthrough
designations. And we've had meetings with the agency, the FDA.

And
I must say that our teams have been just extremely pleased with how the FDA has
worked with us on this product. They've literally not only brought together
people from all disciplines, ranging from clinicians to plant inspectors, to
try to get a coordinated approach to look at every aspect of this product,
every issue that we face, and see how they can help us address those issues.
Not only have they brought those together, but they've even identified,
prospectively issues.

So
rather than not only just responding very well to our questions, they say,
look, here's something that's going to be a concern. Let's think together how
we can get the type of information we need to accelerate this. So it's become a
really active partnership that is identifying problems in advance. The agency
is really marshaling its resources to enable this drug, should it prove to be
as helpful as its current promise suggests it will be, will enable it to get to
patients as quickly as possible.

STEVE
USDIN: And that's something that doesn't routinely happen when you're
submitting a normal application, you don't know exactly what FDA wants, you do
your best to figure it out, you submit the data, and then you see what happens,
right?

DR.
JAY SIEGEL: I think that's right. Now, the agency does have other programs, in
the past, for promising cancer drugs and for promising other drugs -- AIDS -- and
in other areas. And there are opportunities that can accelerate those products.
But the new breakthrough designation is one that's really focusing on a smaller
number of products and really bringing a broad variety of types of resources
together to solve these problems.

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SEGMENT 4

STEVE
USDIN: We're talking with Jay Siegel, a former senior FDA official, about
developing breakthrough drugs. Dr. Siegel, there's going to be two criticisms,
I think, of the breakthrough program. One is, people are going to be concerned
the drugs are going to get out there that haven't been fully tested, that might
be dangerous. And the other is going to be that FDA is collaborating too
closely with companies, that they're too cozy with companies.

What
would be your response to both of those criticisms?

DR.
JAY SIEGEL: Well, with regard to the first, understanding the safety of a drug
is a continuum, a continuous process. There's never for any drug, at any one
point in time, where you know everything you could possibly know about the
safety of the drug. So even after drugs are marketed, all drugs, we continue to
do surveillance.

The
point, then, of breakthrough product, if it truly has the profound and
important benefits to patients who have very serious diseases, not only could
you potentially tolerate more safety concerns, but you could tolerate more
uncertainty about safety. It may not be so important to know precisely the
incidence of something like, say, skin rash or headache if the drug is going to
prolong life.

So
this will enable those products that truly have that type of benefit to get to
the market while we continue to learn about them. As to the agency working with
industry, and I've been on both sides of the coin, the agency and the industry,
each of course, have their own perspectives. And the agency is a regulatory
body. It must regulate industry. But ultimately, it's a public health agency,
and its goal and mission is to advance the health of the public and to protect
the health of the public. And it's quite appropriate for a regulatory body to
help industry understand how to bring forth important new therapies as quickly
and safely as possible.

STEVE
USDIN: So very quickly, also, when we're talking about these therapies, both of
these therapies, they're going to help some patients. They're going to help
some patients a lot. But it's not likely that they're going to be the cure. How
do we get from these kinds of breakthroughs to cures?

Well,
the development of therapies for cancer is a complex process and takes some
time. Typically, as with these drugs, the first studies we're going to do are
in patients who have few other alternatives, very advanced in refractory
disease. When we see good activity and we prove the drugs to be effective for
those patients, then we can start looking at them in more combinations earlier
in the disease instead of currently approved therapies. And that sort of
approach may lead to more and more benefits and hopefully, at the end of the
research process, toward increased cure rates.